2025-01-07 タフツ大学
“We thought, what would happen if we subjected the brain tissue model to a physical disruption, something akin to a concussion?” said Dana Cairns. Photo: Shutterstock
<関連情報>
- https://now.tufts.edu/2025/01/07/head-trauma-may-activate-latent-viruses-brain-leading-neurodegeneration
- https://www.science.org/doi/10.1126/scisignal.ado6430
- https://www.science.org/doi/10.1126/sciadv.aay8828
ヒト脳組織モデルにおいてHSV-1を再活性化することにより、反復傷害がアルツハイマー病に関連する表現型を誘導する Repetitive injury induces phenotypes associated with Alzheimer’s disease by reactivating HSV-1 in a human brain tissue model
Dana M. Cairns, Brooke M. Smiley, Jordan A. Smiley, Yasaman Khorsandian, […], and David L. Kaplan
Science Signaling Published:7 Jan 2025
DOI:https://doi.org/10.1126/scisignal.ado6430
Editor’s summary
Infection with herpes simplex virus type 1 (HSV-1) is common, lifelong, and often in a latent state with periodic reactivation. It is a risk factor for neurodegenerative disease and dementia in some individuals, as are repeated head injuries like concussions. Cairns et al. found that latent HSV-1 was reactivated by repeated mechanical injury to mimic concussions in a three-dimensional human brain tissue model. This mechanism triggered the aggregation of β amyloid and other pathological features associated with neurodegenerative diseases in a manner dependent on the inflammatory cytokine IL-1β. The findings directly link two risk factors in a mechanism that may contribute to dementia-related disease. —Leslie K. Ferrarelli
Abstract
Infection with herpes simplex virus type 1 (HSV-1) in the brains of APOE4 carriers increases the risk of Alzheimer’s disease (AD). We previously found that latent HSV-1 in a three-dimensional in vitro model of APOE4-heterozygous human brain tissue was reactivated in response to neuroinflammation caused by exposure to other pathogens. Because traumatic brain injury also causes neuroinflammation, we surmised that brain injury might similarly reactivate latent HSV-1. Here, we examined the effects of one or more controlled blows to our human brain model in the absence or presence of latent HSV-1 infection. After repeated, mild controlled blows, latently infected tissues showed reactivation of HSV-1; the production and accumulation of β amyloid and phosphorylated tau (which promotes synaptic dysfunction and neurodegeneration); and activated gliosis, which is associated with destructive neuroinflammation. These effects are collectively associated with AD, dementia, and chronic traumatic encephalopathy (CTE) and were increased with additional injury but were absent in mock-infected tissue. Blocking the cytokine IL-1β prevented the induction of amyloid and gliosis in latently infected monolayer cultures after scratch wounding. We thus propose that after repeated mechanical injuries to the brain, such as from direct blows to the head or jarring motions of the head, the resulting reactivation of HSV-1 in the brain may contribute to the development of AD and related diseases in some individuals.
ヘルペス誘発アルツハイマー病の3Dヒト脳類似組織モデル A 3D human brain–like tissue model of herpes-induced Alzheimer’s disease
Dana M. Cairns, Nicolas Rouleau, Rachael N. Parker, Katherine G. Walsh, […], and David L. Kaplan
Science Advances Published:6 May 2020
DOI:https://doi.org/10.1126/sciadv.aay8828
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that causes cognitive decline, memory loss, and inability to perform everyday functions. Hallmark features of AD—including generation of amyloid plaques, neurofibrillary tangles, gliosis, and inflammation in the brain—are well defined; however, the cause of the disease remains elusive. Growing evidence implicates pathogens in AD development, with herpes simplex virus type I (HSV-1) gaining increasing attention as a potential causative agent. Here, we describe a multidisciplinary approach to produce physiologically relevant human tissues to study AD using human-induced neural stem cells (hiNSCs) and HSV-1 infection in a 3D bioengineered brain model. We report a herpes-induced tissue model of AD that mimics human disease with multicellular amyloid plaque–like formations, gliosis, neuroinflammation, and decreased functionality, completely in the absence of any exogenous mediators of AD. This model will allow for future studies to identify potential downstream drug targets for treating this devastating disease.
